What is the initial workup for a patient presenting with macrocytic (large cell) anemia?

Initial Workup for Macrocytic Anemia

The initial workup for macrocytic anemia should include complete blood count with red cell indices, reticulocyte count, peripheral blood smear, vitamin B12 and folate levels, thyroid function tests, and liver function tests. 1

Diagnostic Algorithm

Step 1: Confirm Macrocytosis and Anemia

• Confirm macrocytosis: MCV > 100 fL
• Confirm anemia using WHO criteria:
  • Men: Hemoglobin < 13 g/dL
  • Women: Hemoglobin < 12 g/dL
  • Pregnant women: Hemoglobin < 11 g/dL 1

Step 2: Evaluate Reticulocyte Count

• Low/normal reticulocytes: Indicates ineffective erythropoiesis (most common in macrocytic anemia)
• High reticulocytes (>10 × 10^9/L): Suggests hemolysis or recent hemorrhage; proceed to hemolysis workup (haptoglobin, LDH, bilirubin) 1

Step 3: Examine Peripheral Blood Smear

This critical step helps differentiate between:

• Megaloblastic anemia: Characterized by macro-ovalocytes and hypersegmented neutrophils
• Non-megaloblastic anemia: Normal neutrophil morphology 1

Step 4: Laboratory Testing Based on Smear Results

For Megaloblastic Features:

• Vitamin B12 level
• Serum and RBC folate levels
• If B12 deficiency is confirmed, consider:
  • Anti-intrinsic factor antibodies
  • Anti-parietal cell antibodies
  • Methylmalonic acid (more sensitive than serum B12) 1

For Non-Megaloblastic Features:

• Thyroid function tests (TSH, free T4)
• Liver function tests
• Alcohol use assessment
• Medication review (especially thiopurines, anticonvulsants, methotrexate) 1

Common Causes of Macrocytic Anemia

Megaloblastic Causes:

1. Vitamin B12 deficiency:

   • Pernicious anemia
   • Malabsorption (ileal disease, Crohn's disease)
   • Dietary deficiency (strict vegans)
   • Post-gastrectomy

2. Folate deficiency:

   • Dietary deficiency
   • Malabsorption
   • Increased requirements (pregnancy, hemolysis)
   • Medications (anticonvulsants, methotrexate) 1, 2

Non-Megaloblastic Causes:

1. Alcoholism (most common non-megaloblastic cause)
2. Liver disease
3. Medications: Azathioprine, 6-mercaptopurine, anticonvulsants
4. Hypothyroidism
5. Myelodysplastic syndromes (particularly in elderly patients)
6. Hemolysis or recent hemorrhage (with high reticulocyte count) 3, 4

Special Considerations

When to Consider Myelodysplastic Syndrome (MDS):

• Age > 60 years
• Persistent unexplained macrocytic anemia
• Accompanying cytopenias (leukopenia, thrombocytopenia)
• Dysplastic features on peripheral smear
• Normal B12, folate, and thyroid function 1, 2

False Normal B12 Levels:

Be aware that automated analyzers may report falsely normal or elevated vitamin B12 levels in the presence of anti-intrinsic factor antibodies. If clinical suspicion for B12 deficiency is high despite normal levels, consider:

• Measuring methylmalonic acid and homocysteine levels
• Trial of mecobalamin therapy if typical morphological features are present 5

When to Consider Bone Marrow Examination:

• Unexplained macrocytic anemia after initial workup
• Suspected myelodysplastic syndrome
• Multiple cytopenias
• Abnormal white cells or platelets on peripheral smear 1, 2

Pitfalls to Avoid

1. Missing mixed deficiencies: Iron deficiency can coexist with B12/folate deficiency, resulting in a normal MCV despite megaloblastic changes 1

2. Overlooking medications: Always review all medications, including over-the-counter drugs and supplements 4

3. Assuming all macrocytosis in elderly is MDS: Always rule out reversible causes first 2

4. Relying solely on B12 levels: Consider methylmalonic acid testing when clinical suspicion is high but B12 levels are normal 5

5. Neglecting thyroid function: Hypothyroidism is an important reversible cause of macrocytic anemia 1, 4